Nitroglycerin

Nitroglycerin (NTG) is clinically indicated as initial therapy in nearly all types of myocardial ischemia. Chronic exertional angina, de novo angina, unstable angina, Prinzmetal’s angina (vasospasm), and silent ischemia respond to NTG administration. During intravenous therapy with NTG, if blood pressure (BP) drops and ischemia is not relieved, the addition of phenylephrine will allow coronary perfusion pressure (CPP) to be maintained while allowing higher doses of NTG to be used for ischemia relief. If reflex increases in heart rate (HR) and contractility occur, combination therapy with β-adrenergic blockers may be indicated to blunt this undesired increase in HR. Combination therapy with nitrates and calcium channel blockers may be an effective anti-ischemic regimen in selected patients; however, excessive hypotension and reflex tachycardia may be a problem, especially when a dihydropyridine calcium antagonist is used.

Mechanism of Action

NTG enhances myocardial oxygen delivery and reduces myocardial oxygen demand. NTG is a smooth muscle relaxant that causes vasculature dilation.² Nitrate-mediated vasodilation occurs with or without intact vascular endothelium. Nitrites, organic nitrites, nitroso compounds, and other nitrogen oxide–containing substances (e.g., nitroprusside) enter the smooth muscle cell and are converted to reactive nitric oxide (NO) or S-nitrosothiols, which stimulate guanylate cyclase metabolism to produce cyclic guanosine monophosphate (cGMP) (Fig. 8-1). A cGMP-dependent protein kinase is stimulated with resultant protein phosphorylation in the smooth muscle. This leads to a dephosphorylation of the myosin light chain and smooth muscle relaxation. Vasodilation is also associated with a reduction of intracellular calcium. Sulfhydryl (SH) groups are required for formation of NO and the stimulation of guanylate cyclase. When excessive amounts of SH groups are metabolized by prolonged exposure to NTG, vascular tolerance occurs. The addition of N-acetylcysteine, an SH donor, reverses NTG tolerance. The mechanism by which NTG compounds are uniquely better venodilators, especially at lower serum concentrations, is unknown but may be related to increased uptake of NTG by veins compared with arteries.³

Figure 8-1 Mechanisms of the effects of nitrates in the generation of nitric oxide (NO•) and the stimulation of guanylate cyclase cyclic guanosine monophosphate (GMP), which mediates vasodilation. Sulfhydryl (SH) groups are required for the formation of NO• and the stimulation of guanylate cyclase. Isosorbide dinitrate is metabolized by the liver, whereas this route of metabolism is bypassed by the mononitrates. GTP = guanosine triphosphate.

(Redrawn from Opie LH: Drugs for the Heart, 4th edition. Philadelphia, WB Saunders, 1995, p 33.)

Physiologic Effects

Two important physiologic effects of NTG are systemic and regional venous dilation. Venodilation can markedly reduce venous pressure, venous return to the heart, and cardiac filling pressures. Prominent venodilation occurs at lower doses and does not increase further as the NTG dose increases. Venodilation results primarily in pooling of blood in the splanchnic capacitance system. Mesenteric blood volume increases as ventricular size, ventricular pressures, and intrapericardial pressure decrease.

NTG increases the distensibility and conductance of large arteries without changing systemic vascular resistance (SVR) at low doses. Improved compliance of the large arteries does not necessarily imply afterload reduction. At higher doses, NTG dilates smaller arterioles and resistance vessels, which reduces afterload and BP. Reductions in cardiac dimension and pressure reduce myocardial oxygen consumption () and improve myocardial ischemia. NTG may preferentially reduce cardiac preload while maintaining systemic perfusion pressure, an important hemodynamic effect in myocardial ischemia. However, in hypovolemic states, higher doses of NTG may markedly reduce systemic BP to dangerous levels. A reflex increase in HR may occur at arterial vasodilating doses.

NTG causes vasodilation of pulmonary arteries and veins and predictably decreases right atrial (RAP), pulmonary artery (PAP), and pulmonary capillary wedge pressures (PCWP). Pulmonary artery hypertension may be reduced in various disease states and in congenital heart disease with NTG.

NTG has several important effects on the coronary circulation (Box 8-1). NTG is a potent epicardial coronary artery vasodilator in both normal and diseased vessels. Stenotic lesions dilate with NTG, reducing the resistance to coronary blood flow (CBF) and improving myocardial ischemia. Smaller coronary arteries may dilate relatively more than larger coronary vessels; however, the degree of dilation may depend on the baseline tone of the vessel. NTG effectively reverses or prevents coronary artery vasospasm.

BOX 8-1 Effects of Nitroglycerin and Organic Nitrates on the Coronary Circulation

Modified frgom Abrams J: Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 110(part 2):216, 1985.

• Epicardial coronary artery dilation: small arteries dilate proportionately more than larger arteries

• Increased coronary collateral vessel diameter and enhanced collateral flow

• Improved subendocardial blood flow

• Dilation of coronary atherosclerotic stenoses

• Initial short-lived increase in coronary blood flow, later reduction in coronary blood flow as decreases

• Reversal and prevention of coronary vasospasm and vasoconstriction

Total CBF may initially increase but eventually decreases with NTG despite coronary vasodilation. Autoregulatory mechanisms probably result in decreases in total flow as a result of reductions in wall tension and myocardial oxygen consumption. However, regional myocardial blood flow may improve by vasodilation of intercoronary collateral vessels or reduction of subendocardial compressive forces. Coronary arteriographic studies in humans demonstrate that coronary collateral vessels increase in size after NTG administration. This effect may be especially important when epicardial vessels have subtotal or total occlusive disease. Improvement in collateral flow may also be protective in situations in which coronary artery steal may occur with other potent coronary vasodilator agents. The improvement in blood flow to the subendocardium, the most vulnerable area to the development of ischemia, is secondary to both improvement in collateral flow and reductions in left ventricular end-diastolic pressure (LVEDP), which reduce subendocardial resistance to blood flow. With the maintenance of an adequate CPP (e.g., with administration of phenylephrine), NTG can maximize subendocardial blood flow. The ratio of endocardial to epicardial blood in transmural segments is enhanced with NTG. Inhibition of platelet aggregation also occurs with NTG; however, the clinical significance of this action is unknown.

β-Adrenergic Blockers

β-Adrenergic blockers have multiple favorable effects in treating the ischemic heart during anesthesia (Box 8-3). They reduce oxygen consumption by decreasing HR, BP, and myocardial contractility. HR reduction increases diastolic CBF. Increased collateral blood flow and redistribution of blood to ischemic areas may occur with β-blockers. More free fatty acids may be available for substrate consumption by the myocardium. Microcirculatory oxygen delivery improves, and oxygen dissociates more easily from hemoglobin after β-adrenergic blockade. Platelet aggregation is inhibited. β-Blockers should be started early in ischemic patients in the absence of contraindications. Many patients at high risk of perioperative cardiac morbidity should be started on β-blocker therapy before surgery and continued on this therapy for up to 30 days after surgery.

Perioperative administration of β-adrenergic blockers reduces both mortality and morbidity when given to patients at high risk for coronary artery disease who must undergo noncardiac surgery.⁴ These data suggest that intermediate- and high-risk patients presenting for noncardiac surgery should receive perioperative β-adrenergic blockade to reduce postoperative cardiac mortality and morbidity. Recommendations on the perioperative use of β-adrenergic blockade for noncardiac surgery are given in Box 8-4.

Calcium Channel Blockers

Calcium channel blockers reduce myocardial oxygen demands by depression of contractility, HR, and/or decreased arterial BP.⁷ Myocardial oxygen supply may be improved by dilation of coronary and collateral vessels. Calcium channel blockers are used primarily for symptom control in patients with stable angina pectoris. In an acute ischemic situation, calcium channel blockers (verapamil and diltiazem) may be used for rate control in situations when β-blockers cannot be used. The most important effects of calcium channel blockers, however, may be the treatment of variant angina. These drugs can attenuate ergonovine-induced coronary vasoconstriction in patients with variant angina, suggesting protection via coronary dilation. Most episodes of silent myocardial ischemia, which may account for 70% of all transient ischemic episodes, are not related to increases in myocardial oxygen demands (HR and BP) but, rather, intermittent obstruction of coronary flow likely caused by coronary vasoconstriction or spasm. All calcium channel blockers are effective at reversing coronary spasm, reducing ischemic episodes, and reducing NTG consumption in patients with variant or Prinzmetal’s angina. Combinations of NTG and calcium channel blockers, which also effectively relieve and possibly prevent coronary spasm, are at present rational therapy for variant angina. β-Blockers may aggravate anginal episodes in some patients with vasospastic angina and should be used with caution. Preservation of CBF with calcium channel blockers is a significant difference from the predominant β-blocker anti-ischemic effects of reducing myocardial oxygen consumption.

Calcium channel blockers have proven effective in controlled trials of stable angina. However, rapid-acting dihydropyridines such as nifedipine may cause a reflex tachycardia, especially during initial therapy, and exacerbate anginal symptoms. Such proischemic effects probably explain why the short-acting dihydropyridine nifedipine in high doses produced adverse effects in patients with unstable angina. The introduction of long-acting dihydropyridines such as extended-release nifedipine, amlodipine, felodipine, isradipine, nicardipine, and nisoldipine has led to fewer adverse events. These agents should be used in combination with β-blockers. Some patients may have symptomatic relief improved more with calcium channel blockers than with β-blocker therapy.

Medical Treatment for Hypertension

More than 80 distinct medications are marketed for treatment of hypertension (Table 8-5). Often, combined therapy with two or more classes of antihypertensive medications may be needed to achieve treatment goals (Table 8-6). Although the specific drug selected for initial therapy now has been deemed less important than in the past, recognition that specific antihypertensive drug classes alleviate end-organ damage, beyond that simply associated with reductions in systemic BP, has led to targeted selection of antihypertensive drug combinations on the basis of coexisting risk factors such as recent myocardial infarction, chronic renal insufficiency, or diabetes.¹⁰

Table 8-5 Oral Antihypertensive Drugs

CCB = calcium channel blocker.

^*In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval (trough effect). BP should be measured just before dosing to determine if satisfactory BP control is obtained. Accordingly, an increase in dosage or frequency may need to be considered. These dosages may vary from those listed in the Physicians’ Drug Reference, 51st ed.

† Available now or soon to become available in generic preparations.

Adapted with permission from Chobanian AV, Bakris GL, Black HR, et al: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC-7 Report. JAMA 289:2560, 2003.

Table 8-6 Combination Drugs for Hypertension

BB = β-blocker; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; CCB = calcium channel blocker.

* Some drug combinations are available in multiple fixed doses. Each drug dose is reported in milligrams.

Adapted with permission from Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC-7 Report. JAMA 289:2560, 2003.

Management of Severe Hypertension

For purposes of characterizing treatment urgency, severe hypertension is characterized as either a hypertensive emergency with target organ injury (e.g., myocardial ischemia, stroke, pulmonary edema) or a hypertensive urgency with severe elevations in BP not yet associated with target organ damage. Chronic elevations in BP, even when of a severe nature, do not necessarily require urgent intervention and often may be managed with oral antihypertensive therapy on an outpatient basis. In contrast, a hypertensive emergency necessitates immediate therapeutic intervention, most often in an intensive care setting, with intravenous antihypertensive therapy and invasive arterial BP monitoring. In the most extreme cases of malignant hypertension, severe elevations in BP may be associated with retinal hemorrhages, papilledema, and evidence of encephalopathy, which may include headache, vomiting, seizure, and/or coma. Progressive renal failure and cardiac decompensation are additional clinical features characteristic of the most severe hypertensive emergencies.

The favored parenteral drug for rapid treatment of hypertensive emergencies remains sodium nitroprusside (Table 8-7). An NO donor, sodium nitroprusside induces arterial and venous dilation, providing rapid and predictable reductions in systemic BP. Prolonged administration of large doses may be associated with cyanide or thiocyanate toxicity; however, this is rarely a concern in the setting of acute hypertensive emergencies. Although less potent and predictable than sodium nitroprusside, NTG, another NO donor, may be preferable in the setting of myocardial ischemia or after coronary artery bypass grafting (CABG). NTG preferentially dilates venous capacitance beds as opposed to arterioles; however, rapid onset of tolerance limits the efficacy of sustained infusions to maintain BP control. Nicardipine, a parenteral dihydropyridine calcium channel blocker, and fenoldopam, a selective dopamine-1 (D₁)-receptor antagonist, have been utilized increasingly in select patient populations after CABG and in the setting of renal insufficiency, respectively.¹¹

Table 8-7 Parenteral Drugs for Treatment of Hypertensive Emergencies

Rights were not granted to include this table in electronic media. Please refer to the printed book.

Reproduced with permission from Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 42:1206, 2003.

Several drugs remain available for intermittent parenteral administration in the setting of hypertensive emergencies or urgencies. Hydralazine, labetalol, and esmolol provide additional therapeutic options for intermittent parenteral injection for hypertensive control.

Heart Failure Classification

The ACC/AHA updated guidelines for evaluating and managing heart failure include a new, four-stage classification system emphasizing both the evolution and progression of the disease (Box 8-5). It calls attention to patients with preclinical stages of heart failure to focus on halting disease progression. The staging system is meant to complement, not replace, the widely used New York Heart Association (NYHA) classification, a semiquantitative index of functional classification that categorizes patients with heart failure by the severity of their symptoms. The NYHA classification remains useful clinically because it reflects symptoms, which in turn correlate with quality of life and survival. The new classification system for heart failure, recognizing its progressive course and identifying those who are at risk, reinforces the importance of determining the optimal strategy for neurohormonal antagonism in an attempt to improve the natural history of the syndrome.

Heart failure remains the final common pathway for coronary artery disease, hypertension, valvular heart disease, and cardiomyopathy, in which the natural history results in symptomatic or asymptomatic left ventricular dysfunction. The neurohormonal responses to impaired cardiac performance (salt and water retention, vasoconstriction, sympathetic stimulation) are initially adaptive but, if sustained, become maladaptive, resulting in pulmonary congestion and excessive afterload. This, in turn, leads to a vicious cycle of increases in cardiac energy expenditure and worsening of pump function and tissue perfusion (Table 8-8). Although the cardiorenal and cardiocirculatory branches of this neurohormonal hypothesis of heart failure were the original foundation for the use of diuretics, vasodilators, and inotropes, respectively, seminal information in the early 1990s emerged from large, randomized clinical trials that showed angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, but not most other vasodilators, prolonged survival in patients with heart failure. In a similar fashion, the use of β-blockers, despite their negative inotropic effects, improved morbidity and mortality in randomized controlled trials.

Table 8-8 Neurohormonal Effects of Impaired Cardiac Performance on the Circulation

Modified from Katz AM: Heart failure. In Fozzard HA, Haber E, Jennings RB: The Heart and Cardiovascular System: Scientific Foundations, 2nd ed. New York, Raven, 1992, pp 333-353.

The finding that low-dose aldosterone antagonists added to conventional therapy for heart failure reduced mortality in patients with severe heart failure suggests that there is more to the neurohormonal hypothesis of drug efficacy than cardiorenal and hemodynamic effects alone. Taken together with evidence from basic investigations showing that Ang II is a growth factor and a vasoconstrictor, the clinical data promoted a shift in focus from cardiorenal and cardiocirculatory processes toward cardiac remodeling as the central component in the progression of this neurohormone-mediated cardiac syndrome.¹³ The renin-angiotensin-aldosterone system (RAAS), excess sympathetic activity, endothelin, and various cytokines all have been implicated as stimuli of proliferative signaling that contribute to maladaptive cardiac growth. Accordingly, ventricular remodeling, or the structural alterations of the heart in the form of dilatation and hypertrophy (Box 8-6), in addition to the counterregulatory hemodynamic responses, lead to progressive ventricular dysfunction and represent the target of current therapeutic interventions (Fig. 8-2).

Figure 8-2 Current and future treatments of heart failure. Currently, heart failure therapies are focused on prevention of disease progression with drugs that antagonize neurohormonal systems. Future therapies may involve antagonists of other biologically active systems (e.g., endothelins, TNFα) and anti-remodeling strategies that may reverse the heart failure phenotype. ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; NEP = neutral endopeptidase blocker.

(Adapted from Mann DL. Mechanisms and model in heart failure: A combinatorial approach. Circulation 100:999, 1999.)

Pathophysiologic Role of the Renin-Angiotensin System in Heart Failure

The renin-angiotensin system (RAS) is one of several neuroendocrine systems that are activated in patients with heart failure. The RAS is also an important mediator in the progression of heart failure. In the short term, the juxtaglomerular cells of the kidney release the proteolytic enzyme renin in response to a decrease in BP or renal perfusion (e.g., hemorrhage) generating Ang I from circulating angiotensinogen. ACE cleavage of Ang II from Ang I in the lung produces circulating Ang II. Acutely, Ang II acts as a potent arteriolar and venous vasoconstrictor to return BP and filling pressure to baseline, respectively. Ang II also stimulates the release of aldosterone from the adrenal cortex and antidiuretic hormone from the posterior pituitary. Both contribute to increases in blood volume through their effects on the kidney to promote salt and water reabsorption, respectively. In the long term, elevations in Ang II lead to sodium and fluid retention and increases in systemic vascular resistance, which contribute to symptoms of heart failure, pulmonary congestion, and hemodynamic decompensation (Fig. 8-3).

Figure 8-3 Basic pathway of the renin-angiotensin-aldosterone system (RAAS).

(From Jaski BE: Basis of Heart Failure: A Problem Solving Approach. Boston, Kluwer Academic Publishers, 2000, with kind permission of Springer Science and Business Media.)

In addition to these cardiorenal and cardiocirculatory effects, most of the hormones and receptors of the RAS are expressed in the myocardium, where they contribute to maladaptive growth or remodeling, a key factor in the progression of heart failure. Increased expression of mRNA for angiotensinogen, ACE, and Ang II has been identified in the failing human heart. Correspondingly, increased coronary sinus Ang II concentrations were measured in patients with dilated and ischemic cardiomyopathy, signifying a paracrine or autocrine action of the RAS. Moreover, progressive increases in coronary sinus Ang II production correlated with increases in NYHA functional classification of heart failure. Taken together, these data provide evidence that intracardiac RAS is involved in the evolution of the disease process.

The effects of Ang II on its receptors AT₁ and AT₂ are well appreciated. The AT₁ receptor is involved in several effects that lead to adverse cardiovascular outcomes. Activation of AT₁ receptors promotes aldosterone and vasopressin secretion with concomitant increases in salt and water reabsorption through the kidneys, vasoconstriction, catecholamine release, and cell growth and proliferation of cardiovascular tissue. Stimulation of AT₂ receptors, on the other hand, results in natriuresis, vasodilation, release of bradykinin and NO, and cell growth inhibition or apoptosis. The Ang II that is formed locally in the heart acts primarily through AT₁ receptors located on myocytes and fibroblasts where it participates in the regulation of cardiac remodeling. Through complex cascades of intracellular signal transduction that activate protein transcription factors within the nucleus initiating the creation of RNA transcripts, the long-term effects of intracardiac Ang II on the AT₁ receptor result in cardiomyocyte hypertrophy, fibroblast proliferation, and extracellular matrix deposition (Fig. 8-4). These processes contribute to progressive left ventricular remodeling and left ventricular dysfunction characteristic of heart failure.

Figure 8-4 Left ventricular remodeling stimuli.

Angiotensin-Converting Enzyme Inhibitors

clinical evidence

Evidence supporting the beneficial use of ACE inhibitors in patients with heart failure comes from various randomized, placebo-controlled clinical trials (Table 8-9). Initially this class of drugs was evaluated for treatment of symptomatic heart failure (SOLVD, V-HeFT, CONSENSUS). Patients with NYHA class II to IV heart failure treated with ACE inhibitors had reductions in mortality ranging from 16% to 31%. Subsequently, ACE inhibitors were also found to improve outcome for asymptomatic patients with left ventricular systolic dysfunction in the following categories: patients with ejection fractions less than 35% due to cardiomyopathy, patients within 2 weeks after myocardial infarction with ejection fractions less than 40%, and patients presenting within the first 24 hours of myocardial infarction regardless of ejection fraction. Results from the Heart Outcomes Prevention Evaluation (HOPE) study have further expanded the indications for this class of agents to include asymptomatic, high-risk patients to prevent new-onset heart failure.¹⁴ In patients with diabetes or peripheral vascular disease and an additional atherosclerotic risk factor, but without clinical heart failure or systolic dysfunction, ramipril (10 mg/day) reduced the heart failure risk by 23%. Together, these data endorse the use of ACE inhibitors as first-line therapy for a broad spectrum of patients, including those with left ventricular systolic dysfunction, with or without symptoms, and in high-risk patients with vascular disease and/or diabetes, in addition to those with the traditional coronary risk factors. Since the beginning of these trials, the rationale for the use of ACE inhibitors has expanded from a reduction in the progression of clinical heart failure through ACE inhibitor–mediated vasodilatory action to acknowledgment that ACE inhibitors also directly affect the cellular mechanisms responsible for progressive myocardial pathology.

Table 8-9 Selected Clinical Trials of Angiotensin-Converting Enzyme Inhibitors in Heart Failure

mechanisms of action

ACE inhibitors act by inhibiting one of several proteases responsible for cleaving the decapeptide, Ang I, to form the octapeptide Ang II. Because ACE is also the enzyme that degrades bradykinin, ACE inhibitors lead to increased circulating and tissue levels of bradykinin (Fig. 8-5). ACE inhibitors have several useful effects in chronic heart failure. They are potent vasodilators through decreasing Ang II and norepinephrine and increasing bradykinin, NO, and prostacyclin. By reducing the secretion of aldosterone and antidiuretic hormone (ADH), ACE inhibitors also reduce salt and water reabsorption from the kidney. ACE inhibitors reduce release of norepinephrine from sympathetic nerves by acting on AT₁ receptors at the nerve terminal. Within tissue, ACE inhibitors inhibit Ang II production and thus attenuate Ang II-mediated cardiomyocyte hypertrophy and fibroblast hyperplasia. Clinical evidence supporting an ACE inhibitor-mediated role in cardiac remodeling comes from comparative studies of enalapril versus placebo (SOLVD trial) and enalapril versus hydralazine isosorbide dinitrate (VHeft II trial).

Figure 8-5 Activation of the renin-angiotensin-aldosterone system (RAAS).

(Redrawn from Mann DL. Heart Therapy: A Companion to Braunwald’s Heart Disease. Philadelphia: Saunders, 2004.)

ACE inhibitors attenuate insulin resistance, a common metabolic abnormality in heart failure patients, independent of Ang II activity. Ang II receptor antagonists do not attenuate insulin resistance. Both ACE inhibitors and angiotensin-receptor blockers have been shown to reduce proteinuria, and slow the progression to renal failure in hypertensives (and a common comorbidity in heart failure patients).

β-Adrenergic Receptor Antagonists

Adjunctive Drugs

In addition to ACE inhibitors and β-blockers, diuretics and digoxin are often prescribed for patients with left ventricular systolic dysfunction and symptomatic heart failure.

Future Therapy

Among the promising nonpharmacologic therapies for the management of heart failure are the implantable defibrillators and biventricular pacemakers. In the COMPANION trial (The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure), cardiac resynchronization therapy with a pacemaker combined with an implantable defibrillator significantly decreased the likelihood of death from or hospitalization for heart failure when compared with conventional pharmacologic therapy.²⁰

Stem cell therapy is another potential treatment of heart failure. Stem cell therapy has shown promise in the treatment of ischemic heart disease both in the laboratory and in small clinical studies. Autologous bone marrow and peripheral blood stem cells transplanted in patients with acute myocardial infarction improved cardiac function. However, until double-blind, randomized controlled trials are performed, the true benefit of this innovative treatment remains unknown.

Management of Acute Exacerbations of Chronic Heart Failure

Patients with chronic heart failure, despite good medical management, may experience episodes of pulmonary edema or other signs of acute volume overload. These patients may require hospitalization for intensive management if diuretics fail to relieve their symptoms. Other patients may experience exacerbations of heart failure associated with acute myocardial ischemia or infarction, worsening valvular dysfunction, infections (including myocarditis), or failure to maintain an established drug regimen. Fonarow and associates described a risk stratification system for in-hospital mortality in acutely decompensated heart failure using data from a national registry. Low-, intermediate-, and high-risk patients with mortality ranging from 2.1% to 21.9% were identified using blood urea nitrogen, creatinine, and systolic BP on admission. These patients will require all the standard medications, as outlined in previous sections, and may also require infusions of vasodilators or positive inotropic drugs.²¹

Low-Output Syndrome

Acute heart failure is a frequent concern of the cardiac anesthesiologist, particularly at the time of separation from cardiopulmonary bypass (CPB). The new onset of ventricular dysfunction and a low CO state after aortic clamping and reperfusion is a condition with more pathophysiologic similarity to cardiogenic shock than to chronic heart failure and is typically treated with positive inotropic drugs, vasopressors (or vasodilators), if needed, and/or mechanical assistance. The latter more commonly takes the form of intra-aortic balloon counterpulsation and less commonly includes one of the several available ventricular assist devices.

Pharmacologic Treatment of Diastolic Heart Failure

Abnormal diastolic ventricular function is a common cause of clinical heart failure. As many as one in three patients presenting with clinical signs of chronic heart failure has a normal or near-normal ejection fraction (≥40%). The risk of diastolic heart failure increases with age, approaching 50% in patients older than 70 years old. Diastolic heart failure is also more common in females and in patients with hypertension or diabetes mellitus. Although the prognosis of patients with diastolic heart failure is better than for systolic heart failure (5% to 8% vs. 10% to 15% annual mortality, respectively), the complication rate is the same. The 1-year readmission rate for patients with isolated diastolic heart failure approaches 50%.

In contrast to the large randomized trials that have led to the treatment guidelines for systolic heart failure, there are few randomized, double-blind, placebo-controlled, multicenter trials performed in patients with diastolic heart failure. Consequently, the guidelines are based on clinical experience, small clinical studies, and an understanding of the pathophysiologic mechanisms. The general approach to treating diastolic heart failure has three main components. First, treatment should reduce symptoms, primarily by lowering pulmonary venous pressure during rest and exercise by reducing left ventricular volume, maintaining AV synchrony, and increasing the duration of diastole by reducing HR. Second, treatment should target the underlying causes of diastolic heart failure. Specifically, ventricular remodeling should be reversed by controlling hypertension, replacing stenotic aortic valves, and treating ischemia. Third, treatment should target the underlying mechanisms that are altered by the disease processes, mainly neurohormonal activation. Drug treatment of diastolic heart failure with respect to these three goals is shown in Table 8-10.

Table 8-10 Diastolic Heart Failure Treatments